Age is the most important risk factor for developing neurodegenerative disorders such as Alzheimer's disease. However, the mechanisms controlling the special vulnerability of the aging nervous system to neurodegenerative stimuli remain undefined. We have previously documented a clear age-dependence of neurodegeneration in the Drosophila models of human neurodegenerative diseases that we have developed, including models relevant to Parkinson's disease and Alzheimer's disease. We will now use a powerful new regulated gene expression system to direct expression of toxic proteins related to human neurodegenerative diseases specifically to either the young or aged nervous system for defined periods of time. These experiments will allow us to test the hypothesis that the age-dependence of neurodegenerative diseases represents a selective vulnerability of older neurons. Alternatively, we may find that the increased prevalence of neurodegenerative diseases in older individuals represents the prolonged presence of a neurodegenerative stimulus within the long lived neuron. If we find that older neurons are indeed more vulnerable to toxic proteins related to Alzheimer's disease, Parkinson's disease and related disorders we will then be in the position to determine what feature of the aging nervous system endows selective vulnerability to these stimuli. There are well documented changes in the oxidative stress system and the ubiquitin/proteasome system and these systems have been implicated in the pathogenesis of neurodegenerative disorders. Genetic reagents that target these systems will thus first be used to determine the specific pathways that underlie the age-dependence of neurodegeneration. These studies have the potential to define the mechanisms underlying the specific vulnerability of the aged nervous system to neuronal death. Relevance: Neurodegenerative diseases like Alzheimer's disease and Parkinson's disease represent a devastating burden on our aging population, care takers and health care resources. These diseases are remarkable in that they preferentially target older individuals. The studies outlined in this proposal will determine if older neurons have undergone specific cellular changes that make them more vulnerable to neurodegeneration and will outline the pathways responsible for age-dependent vulnerability. Pathways critical for these vulnerabilities will provide important therapeutic targets. [unreadable] [unreadable] [unreadable]